Elevations of circulating glucocorticoid levels have been associated with mild to severe cognitive deficits (e.g., memory; see Alderson & Novack, 2002). Such effects have been observed following administration of glucocorticoid medications but also as result of prolonged stress and some forms of depression. Moreover, these effects have been observed in children treated for asthma with glucocorticoids (Bender et al., 1988; Nadel, personal communication, October, 2002). The cognitive impairments described appear to be largely mediated by the hippocampus (Nadel, personal communication, October, 2002; Nelson, 2000; Newcomer et al., 1994; Sapolsky et al., 2000; Young et al., 1999). This link between increased glucocorticoid levels, the hippocampus and cognitive dysfunction, together with the higher incidence of several neurodevelopmental disorders in males over females, suggests that the developing male brain may be more vulnerable to glucocorticoid-induced injury (e.g., Kapoor & Matthews, 2005; Matthews, 2001; Ramsden et al., 2003). For this reason, it is important to understand not only how early exposure to glucocorticoids may affect hippocampal development and later learning, but also potential sex differences in these effects. [unreadable] [unreadable] We have shown previously (Claflin et al., 2005) that post- stress hypo-responsive period administration of corticosterone (CORT) impairs acquisition of trace eyeblink conditioning (EBC) in male rats but not females. The proposed studies seek to: (1) ....identify the lowest dose of CORT that, when administered with osmotic minipumps at a constant dose over 3 days, will produce a later deficit in learning trace EBC in males. (2) ....examine cells in the dentate gyrus and CA regions of hippocampus in rats that were treated with CORT at a young age, using fluorescent immunohistochemical co-labeling with NeuN and BrdU, in order to see if there are neuroanatomical differences that can explain the behavioral effects observed. We will also evaluate whether engaging the hippocampus in a learning task can increase the survivability of new neurons. (3) ....determine whether choline supplementation is a possible treatment or neuroprotectant that can reverse or attenuate the detrimental effects of CORT on learning in male rats. PUBLIC HEALTH RELEVANCE: The studies proposed here aim to understand the effects of elevated glucocorticoids early in development on maturation of the brain and learning processes. Because glucocorticoid medications are used to treat respiratory diseases, including asthma, in young children, it is important to understand what the lasting effects of such treatments may be. Moreover, glucocorticoids appear to affect brain function and behavior differently in males and females. Learning more about these differences may help us understand why certain neurodevelopmental disorders (e.g., autism) are more prevalent in males vs. females. [unreadable] [unreadable] [unreadable] [unreadable] [unreadable] [unreadable]